U.S. patent number 11,027,218 [Application Number 16/308,421] was granted by the patent office on 2021-06-08 for purification and separation techniques for cannabinoids.
This patent grant is currently assigned to Canopy Growth Corporation. The grantee listed for this patent is Canopy Growth Corporation. Invention is credited to Karl Enmark, Kurt Aron Levy.
United States Patent |
11,027,218 |
Levy , et al. |
June 8, 2021 |
Purification and separation techniques for cannabinoids
Abstract
This disclosure relates to techniques and methods to isolate and
purify cannabinoids, such as CBDV, CBD, CBC, THCV, THC, CBN, CBG,
CBDA, THCA, or CBGA. Evaporation and sonicating techniques are used
to isolate and purify cannabinoids, such as CBDV, CBD, CBC, THCV,
THC, CBN, CBG, CBDA, THCA, or CBGA. The resulting compounds find
further use within the devices and compositions described herein as
well as for preparative and analytical methods.
Inventors: |
Levy; Kurt Aron (Dillon,
CO), Enmark; Karl (Lakewood, CO) |
Applicant: |
Name |
City |
State |
Country |
Type |
Canopy Growth Corporation |
Ontario |
N/A |
CA |
|
|
Assignee: |
Canopy Growth Corporation
(Ontario, CA)
|
Family
ID: |
60578158 |
Appl.
No.: |
16/308,421 |
Filed: |
June 9, 2017 |
PCT
Filed: |
June 09, 2017 |
PCT No.: |
PCT/US2017/036792 |
371(c)(1),(2),(4) Date: |
December 07, 2018 |
PCT
Pub. No.: |
WO2017/214529 |
PCT
Pub. Date: |
December 14, 2017 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20190192993 A1 |
Jun 27, 2019 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62508129 |
May 18, 2017 |
|
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62348445 |
Jun 10, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01D
11/0292 (20130101); B01D 9/0018 (20130101); C07C
39/23 (20130101); B01D 15/40 (20130101); C30B
7/00 (20130101); B01D 11/0288 (20130101); C07C
39/19 (20130101); B01D 11/0207 (20130101); B01D
11/02 (20130101); B01D 11/0265 (20130101); C07D
311/80 (20130101); C30B 29/54 (20130101); B01D
9/00 (20130101) |
Current International
Class: |
B01D
11/02 (20060101); C30B 29/54 (20060101); C07D
311/80 (20060101); B01D 15/40 (20060101); C07C
39/19 (20060101); C07C 39/23 (20060101); C30B
7/00 (20060101); B01D 9/00 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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104277917 |
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Jan 2015 |
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CN |
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WO-2016187679 |
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Dec 2016 |
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WO |
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Primary Examiner: Kenyon; John S
Attorney, Agent or Firm: Sheridan Ross P.C.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Stage application under 35 U.S.C.
371 of International Application No. PCT/US2017/036792 having an
international filed date of Jun. 9, 2017 which claims priority on
the basis of U.S. Provisional Patent Application Ser. No.
62/348,445, filed on Jun. 10, 2016 and U.S. Provisional Patent
Application Ser. No. 62/508,129, filed on May 18, 2017, each of
which is hereby incorporated by reference.
Claims
What is claimed is:
1. A method of purifying one or more cannabinoids from a plant
material of genus cannabis, comprising: adding the plant material
of genus cannabis to ethanol; sonicating the ethanol and plant
material of genus cannabis at a temperature of between about -80 to
30 degrees Celsius; dissolving cannabinoids in the ethanol to
create a solution of cannabinoids; physically separating the plant
material of genus cannabis from the solution comprising
cannabinoids; and evaporating the ethanol from the solution at a
pressure of less than 1 atmosphere.
2. The method of claim 1, comprising sonicating the ethanol and
plant material of genus cannabis at a temperature of between about
-50 to 10 degrees Celsius.
3. The method of claim 2, comprising sonicating the ethanol and
plant material of genus cannabis at a temperature of between about
-30 to -10 degrees Celsius.
4. The method of claim 1, comprising evaporating the ethanol from
the solution at a temperature of between about 20 to 60 degrees
Celsius.
5. The method of claim 1, comprising collecting a precipitated
cannabinoid from within an ethanolic solution of cannabinoids.
6. The method of claim 5, comprising dissolving the precipitated
cannabinoid in an alcohol, creating a second solution, then
recrystallizing the precipitated cannabinoid from the second
solution.
7. The method of claim 6, comprising evaporating alcohol from the
second solution.
8. The method of claim 6, wherein the alcohol is ethanol.
Description
TECHNICAL FIELD
This disclosure relates to the cannabis industry. In particular,
this relates to purification and separation techniques.
BACKGROUND
The word "cannabis" refers to a genus of flowering plants. Plants
of genus cannabis include several species, including Cannabis
sativa, Cannabis indica, and Cannabis ruderalis. There is a long
history of cultivating plants of genus cannabis for hemp fibers,
seeds and seed oils, medicinal purposes, and recreational
activities.
According to some accounts, cannabis is composed of at least 483
known chemical compounds, which include cannabinoids, terpenoids,
flavonoids, nitrogenous compounds, amino acids, proteins,
glycoproteins, enzymes, sugars and related compounds, hydrocarbons,
alcohols, aldehydes, ketones, acids, fatty acids, esters, lactones,
steroids, terpenes, non-cannabinoid phenols, vitamins, and
pigments.
Cannabinoids are of particular interest for research and
commercialization. Most extractions of cannabis plant matter aim to
extract cannabinoids, particularly tetrahydrocannabinol (THC). THC
is useful for relieving pain, treating glaucoma, and relieving
nausea. THC is also gaining immense popularity as a recreational
drug substance. Usually, cannabinoids are extracted from the
cannabis plant as part of a crude mixture, combined with other
chemical compounds found in the cannabis plant.
Many extraction processes have been developed for isolating and
purifying these cannabinoids. But there has been difficulty in
isolating individual cannabinoids at high levels of purity, both
for active ingredients for use in medicine and product
manufacturing and/or as standards for use in research and
development. Gas chromatography has provided adequate samples of
some cannabinoids, like THC, CBD, and CBN on a smaller scale. For
larger preparative scales, methods of extraction include lipid
extraction and butane hash oil (BHO) extraction.
In these existing methods, there exists variability and
inconsistency with regards to which molecules are extracted from
the plant. Accordingly, extractions vary considerably in chemical
composition depending on the variety of plant used in the
extraction and the extraction parameters used to purify the
cannabinoid compounds.
There exists a need for separation techniques that yields a high
purity of cannabinoids. There exists a need for separation and
extraction techniques which provide reliable and consistent
purified cannabinoid compositions. In particular, there exists a
need for isolating purified cannabinoids on a scalable level.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 illustrates a non-limiting example of the resolution of
separating 10 cannabinoids using the methods disclosed herein.
FIG. 2 illustrates a non-limiting example of the purification of
CBD using the methods disclosed herein.
FIG. 3 illustrates a non-limiting example of the purification of
THC using the methods disclosed herein.
FIG. 4 illustrates a non-limiting example of axial gradients during
SFC using the methods disclosed herein.
DETAILED DESCRIPTION
Disclosed herein are new methods for purifying and separating one
or more compounds from a plant of genus cannabis. In one
embodiment, this disclosure provides a method of purifying a
cannabinoid from a plant of genus cannabis. In one embodiment, this
disclosure provides a method of purifying a terpene from a plant of
genus cannabis. In one embodiment, this disclosure provides a
method of purifying and separating a collection of cannabinoids
from a plant of genus cannabis. In one embodiment, this disclosure
provides a method of purifying and separating a collection of
terpenes from a plant of genus cannabis. In one embodiment, this
disclosure provides a method of purifying and separating a
collection of cannabinoids and terpenes from a plant of genus
cannabis.
In one embodiment, a cannabinoid is isolated from a plant of genus
cannabis by sonication, extraction, and/or evaporation techniques.
In some embodiments, extraction of a high purity cannabinoid is
accomplished by applying a range of extraction temperatures. The
purifying and separating techniques disclosed herein are scalable.
In some embodiments, extraction of a high purity cannabinoid is
accomplished on an analytical scale. In some embodiments,
extraction of a high purity cannabinoid is accomplished on a
preparative scale.
Additionally, Cellulose-2 is available in 3, 5, 10, and 20 .mu.m
particle size allowing for scalability of the disclosed methods at
various levels of preparative scale. A chromatographer can use a
pre-packed Axia preparative column, up to 50 mm diameter, or
manually pack a column for further scale-up and large scale
manufacturing production.
In one embodiment, the purifying and separating techniques comprise
column chromatography. In one embodiment, the column length and
particle size are held constant while the column diameter is
increased.
In one embodiment, the particle size is between 1-20 .mu.m.
In one embodiment, the particle size is between 3-25 .mu.m.
In one embodiment, the particle size is between 5-15 .mu.m.
Disclosed herein is a new product made from the aforementioned
methods. In one embodiment, the product is suitable for formulating
compositions. In one embodiment, the product is suitable as an
analytical standard.
Disclosed herein is a new method of purifying secondary compounds,
e.g., a cannabinoid, terpene, etc., from plant material,
comprising:
adding the plant material to alcohol;
sonicating the alcohol and plant material;
dissolving secondary compounds in the alcohol to create a solution
of secondary compounds;
physically separating the plant material from the solution
comprising secondary compounds; and
evaporating the alcohol from the solution.
As used herein, the term "purifying" means separating, extracting,
and/or isolating a compound or compounds from other compounds,
materials, matter, mass and/or substances. For example, within the
context of this disclosure, the term "purifying" includes
extracting or separating from other compounds, compositions,
matter, or mass. For example, individual cannabinoid compounds
"purified" vis-a-vis those occurring in the cannabis plant are
separated from some or all other parts of the plant. In one
embodiment, purifying provides a compound or compounds having
purity significantly different than from crude extracts, a
biological drug substance (BDS), plant matter, or formulations and
compositions made from the same.
In one embodiment, the term purifying refers to separating a
cannabinoid from the plant matter from which it was derived. In one
embodiment, the purifying refers to separating a cannabinoid from
other cannabinoids present in the plant matter from which it was
derived. In one embodiment, the term purifying refers to separating
a cannabinoid from terpenes present in the plant matter from which
it was derived. In one embodiment, the term purifying refers to
separating a cannabinoid from secondary compounds present in the
plant matter from which it was derived. In one embodiment, the term
purifying refers to separating a cannabinoid from all material that
was present in the plant matter from which it was derived.
In one embodiment, the term purifying refers to separating a
terpene from the plant matter from which it was derived. In one
embodiment, the purifying refers to separating a terpene from other
terpenes present in the plant matter from which it was derived. In
one embodiment, the term purifying refers to separating a terpene
from cannabinoids present in the plant matter from which it was
derived. In one embodiment, the term purifying refers to separating
a terpene from secondary compounds present in the plant matter from
which it was derived. In one embodiment, the term purifying refers
to separating a terpene from all material that was present in the
plant matter from which it was derived.
Within the context of this disclosure, purified compounds may be
purposely formulated with other compounds at various levels of
purity. For example, depending on the desired outcome, a particular
cannabinoid or terpene may be formulated with other molecules when
it is 60-65% pure, 65-70% pure, 70-75% pure, 75-80% pure, 80-85%
pure, 85-90% pure, 90-95% pure, 95-99% pure, 99-99.9% pure, 99.9+%,
or greater than 99% pure. Provided that the ingredients used for
purposeful formulation are purified prior to the said purposeful
formulation, the act of subsequently formulating them does render
them not "purified" within the context of an ingredient list.
In one embodiment, the compounds disclosed herein are purified by
extracting the soluble compounds from plant material with
ethanol.
In one embodiment, the compounds disclosed herein are purified
through chromatography techniques, such as supercritical fluid
chromatography.
In one embodiment, the purity of a purified cannabinoid is
determined by chromatography, such as HPLC, GC-MS, or other known
analytical methods.
In one embodiment, a cannabinoid and/or a terpene is purified from
natural plant of genus cannabis by using a Novasep SuperSep 1000
preparative Supercritical Fluid Chromatography System, configured
to collect fractions, each containing one or more of a cannabinoid
or terpene.
In one embodiment, a cannabinoid and/or a terpene is purified from
a natural plant of genus cannabis via chromatography on a
polysaccharide-based stationary phase, e.g., cellulose column,
e.g., 5 .mu.m 250.times.4.6 mm cellulose column of Cellulose
tris(3-chloro-4-methylphenylcarbamate).
In one embodiment, a cannabinoid and/or terpene is purified using a
Jasco 50 preparative Supercritical Fluid Chromatography System. In
one embodiment, the system is configured with open bed collection.
In one embodiment, the system is configured to collect greater than
10 fractions. In one embodiment, the system is configured to
collect greater than 20 fractions. In one embodiment, the system is
configured to collect greater than 50 fractions. In one embodiment,
the system is configured to collect greater than 100 fractions.
In one embodiment, a cannabinoid is purified by chromatography
using a CO2/ethanol gradient program.
In one embodiment, one or more cannabinoids are separated by
chromatography and eluted from the column in the following order
CBD; CBC; THCV; THC; CBN; CBG; CBDA; and THCA.
In one embodiment, one or more cannabinoids are separated by
chromatography and eluted from the column in the following order
CBDV; CBD; CBC; THCV; THC; CBN; CBG; CBDA; THCA; and CBGA.
In one embodiment, CBD is purified from hemp extract by using a
250.times.10 mm cellulose column with ethanol as an organic
modifier under supercritical fluid chromatography conditions. In
one embodiment, acidic cannabinoids, e.g., CBDA, THCA, CBDA, etc.,
are eluted at the end of the separation run, i.e., in the later
fractions.
In one embodiment, THC is purified from a plant of genus cannabis
on an analytical scale, e.g., 250.times.4.6 mm cellulose column. In
one embodiment, THC is purified from a plant of genus cannabis on a
preparative scale, e.g., 250.times.50 mm cellulose column.
As used herein, the term "plant material" means mass that is
generated by a growing plant, including any compound or compounds
(for example one or more secondary compounds) which may be later
isolated. In one embodiment, the plant material is the stem of a
plant. In one embodiment, the plant material is a trichome. In one
embodiment, the plant material is a leaf. In one embodiment, the
plant material is a flower. In one embodiment, the plant material
is a whole plant. In one embodiment, the plant material is dried.
In one embodiment, the dried plant material is ground.
As used herein, the term "alcohol" means an organic compound with a
hydroxyl group attached to a carbon atom. In one embodiment, the
alcohol is methanol. In one embodiment, the alcohol is ethanol. In
one embodiment, the alcohol is propanol. In one embodiment, the
alcohol is butanol.
As used herein, the term "sonicating" means using sound energy to
agitate a particular portion of mass, for example by submerging a
solid (e.g., plant material) into a liquid bath and then applying
sound energy to the bath with the plant material in it.
As used herein, the term "dissolving" means incorporating a solid
or gas substance into a liquid to create a homogenous liquid. In
one embodiment, dissolving comprises heating. In one embodiment,
dissolving comprises stirring. In one embodiment, dissolving
comprises mixing. In one embodiment, dissolving comprises
sonicating.
As used herein, the term "solution" means a homogeneous liquid
having one or more molecular substances included therein. In one
embodiment, the solution is a mixture of an alcohol and plant
material. In one embodiment, the solution is a mixture of an
alcohol and at least one cannabinoid. In one embodiment, the
solution is a mixture of an alcohol and a at least one terpene.
As used herein, the term "evaporating" means transforming a
substance from the liquid phase to the gas phase. In one
embodiment, evaporating comprises heating. In one embodiment,
evaporating comprises manipulating pressure.
In one embodiment, the methods disclosed herein comprise
evaporating the alcohol from the solution at a pressure of less
than 1 atmosphere.
In one embodiment, the methods disclosed herein comprise sonicating
the alcohol and plant material at a temperature of between about
-80 to 30 degrees Celsius.
In one embodiment, the methods disclosed herein comprise sonicating
the alcohol and plant material at a temperature of between about
-50 to 10 degrees Celsius.
In one embodiment, the methods disclosed herein comprise sonicating
the alcohol and plant material at a temperature of between about
-30 to -10 degrees Celsius.
In one embodiment, the methods disclosed herein comprise sonicating
the alcohol and plant material at a temperature of between about 20
to 60 degrees Celsius.
In one embodiment, the methods disclosed herein comprise collecting
a precipitated cannabinoid from within an alcoholic solution of
secondary compounds. In one embodiment, the cannabinoid is selected
from: CBDV, CBD, CBC, THCV, THC, CBN, CBG, CBDA, THCA, or CBGA.
As used herein, the term "CBDV" refers to Cannabidivarin, which has
the following structural formula:
##STR00001##
As used herein, the term CBD refers to Cannabidiol, which has the
following structural formula:
##STR00002##
As used herein, the term "CBC" refers to Cannabichromene, which has
the following structural formula:
##STR00003##
As used herein, the term "THCV" refers to Tetrahydrocannabivarin,
THV, THCv, THC-V, etc., which has the following structural
formula:
##STR00004##
As used herein, the term "THC" refers to Tetrahydrocannabinol,
which has the following structural formula:
##STR00005##
As used herein, the term "CBN" refers to Cannabinol, which has the
following structural formula:
##STR00006##
As used herein, the term "CBG" refers to Cannabigerol, which has
the following structural formula:
##STR00007##
As used herein, the term "CBDA", "CBD-A", "CBDa", etc. refers to
Cannabidiolic Acid, which has the following structural formula:
##STR00008##
As used herein, the term "THCA", "THC-A", "THCa", etc., refers to
Tetrahydrocannabinolic Acid, which has the following structural
formula:
##STR00009##
As used herein, the term "CBGA", "CBG-A", "CBGa", etc., refers to
Cannabigerolic Acid, which has the following structural
formula:
##STR00010##
As used herein, the term "precipitated cannabinoid" refers to a
solid forming within and falling out of a liquid solution. In one
embodiment, the precipitated cannabinoid forms by changing the
temperature. In one embodiment, the precipitated cannabinoid forms
by using a saturated solution. In one embodiment, the precipitated
cannabinoid is selected from: CBDV, CBD, CBC, THCV, THC, CBN, CBG,
CBDA, THCA, or CBGA.
In one embodiment, the methods disclosed herein comprise collecting
the precipitated cannabinoid in an alcohol, creating a second
solution, then recrystallizing the cannabinoid from the second
solution.
As used herein, the term "recrystallizing" means to crystallize, or
precipitate, a solid substance. In one embodiment, recrystallizing
comprises dissolving a solid into a liquid and crystallizing the
solid at least a second time. Typically, recrystallizing a
substance results in higher purity.
In one embodiment, the methods disclosed herein comprise dissolving
the precipitated cannabinoid in an alcohol, creating a second
solution, then recrystallizing the cannabinoid from the second
solution. In one embodiment, the alcohol is evaporated. In one
embodiment, the alcohol is ethanol.
Disclosed herein is a new product produced by the method of
purifying compounds from plant material, comprising:
adding the plant material to alcohol;
sonicating the alcohol and plant material;
dissolving one or more compounds in the alcohol to create a
solution of secondary compounds;
physically separating the plant material from the solution
comprising secondary compounds; and
evaporating the alcohol from the solution.
In one embodiment, the products disclosed herein comprise a single
crystal. In one embodiment, the products disclosed herein comprise
a single crystal of a cannabinoid. In one embodiment, the
cannabinoid is selected from: CBDV, CBD, CBC, THCV, THC, CBN, CBG,
CBDA, THCA, or CBGA.
As used herein, the term "single crystal" means the crystal lattice
of the entire sample is continuous and unbroken to the edges of the
sample, with no grain boundaries.
In one embodiment, the single crystal of a cannabinoid is suitable
for x-ray diffraction.
As used herein, the term "x-ray diffraction" refers to a rapid
analytical technique primarily used for phase identification of a
crystalline material and can provide information on unit cell
dimensions.
Disclosed herein is a composition comprising a precipitated
cannabinoid from within an alcoholic solution of secondary
compounds.
Disclosed herein is a device comprising the product produced by the
method of purifying secondary compounds from plant material,
comprising:
adding the plant material to alcohol;
sonicating the alcohol and plant material;
dissolving secondary compounds in the alcohol to create a solution
of secondary compounds;
physically separating the plant material from the solution
comprising secondary compounds; and
evaporating the alcohol from the solution, and attaching the
resulting solid to a rigid support.
As used herein, a "rigid support" means a stiff structure
supporting substance.
In one embodiment, the devices disclosed herein comprise a rigid
transparent vessel;
wherein said product is contained within said rigid transparent
vessel; and
wherein said rigid support means is contained within said rigid
transparent vessel.
As used herein, a "rigid transparent vessel" means a firm storage
device that is see through.
In one embodiment the devices comprise between 0.1 to 1.0 grams of
the said product.
FIG. 1 illustrates one example of the resolution achieved by the
disclosed methods using a Lux Cellulose-2 analytical column for
separating 10 cannabinoids. Separating the cannabinoid standards
with a baseline resolution was accomplished in less than 12 minutes
on a 250.times.4.6 mm analytical column.
The disclosed method provides for optimization for specific
cannabinoids. A smaller particle size, such as 3 .mu.m, contributes
to improved resolution and speed of analysis.
Chromatography also provides the ability for preparing the
development work on a 250.times.4.6 analytical column. Then,
keeping critical parameters, e.g., column packing, and conditions
consistent, scale-up equations allow for scaling the separation
method.
FIG. 2 illustrates a non-limiting example of purifying CBD from
hemp extract using a Lux 5 um Cellulose-2 250.times.10 mm with
ethanol as an organic modifier under SFC conditions.
The cycle time was 7 minutes and collected fractions were
represented on a preparative chromatogram.
FIG. 3 illustrates a non-limiting example of a separating THC from
other molecules found in cannabis. The separation technique was
developed on a 250.times.4.6 mm analytical column and scaled-up to
a 250.times.50 mm Axia packed preparative column using a scale-up
equation to preserve separation parameters.
One method for achieving predictable scale-up from a bench-top
instrument to a production instrument, including maintaining the
column length and particle size while increasing the column
diameter. This approach preserves the intrinsic conditions between
4.6 and 50 mm diameter columns. FIG. 4 illustrates a non-limiting
example of typical axial gradients occurring during the methods
disclosed herein.
EXAMPLES
The Cellulose-2 stationary phase was used for separating 10
cannabinoids (CBDV, CBD, CBC, THCV, THC, CBN, CBG, CBDA, THCA, and
CBGA).
By using the Cellulose-2 stationary phase, the acid cannabinoids
such as CBDA, THCA, and CBGA are eluted at the end of the
separation under SFC conditions with ethanol as an organic
modifier.
For purification on a column >50 mm ID, a bulk media was packed
in a Dynamic Axial Compression (DAC) column. Lux Cellulose-2 was
used with either 10 or 20 .mu.m particle size. In some instances,
the 10 .mu.m particle size was a good compromise for batch
processes using a single column.
Another example of the methods disclosed herein comprises
separating 10 cannabinoids in less than 15 minutes by using SFC and
a Lux Cellulose-2 column. This method was optimized for each
cannabinoid by modifying the separation conditions.
The above examples are for illustrative purposes and are not meant
to limiting or excluding subject matter.
Although the present invention herein has been described with
reference to various exemplary embodiments, it is to be understood
that these embodiments are merely illustrative of the principles
and applications of the present invention. Those having skill in
the art would recognize that various modifications to the exemplary
embodiments may be made, without departing from the scope of the
invention.
Moreover, it should be understood that various features and/or
characteristics of differing embodiments herein may be combined
with one another. It is therefore to be understood that numerous
modifications may be made to the illustrative embodiments and that
other arrangements may be devised without departing from the scope
of the invention.
Furthermore, other embodiments of the invention will be apparent to
those skilled in the art from consideration of the specification
and practice of the invention disclosed herein. It is intended that
the specification and examples be considered as exemplary only,
with a scope and spirit being indicated by the claims.
Finally, it is noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and "the," include
plural referents unless expressly and unequivocally limited to one
referent, and vice versa.
As used herein, the term "include" or "comprising" and its
grammatical variants are intended to be non-limiting, such that
recitation of an item or items is not to the exclusion of other
like items that can be substituted or added to the recited
item(s).
* * * * *